Plasma and urine histamine levels were determined in patients with systemic mastocytosis, urticaria pigmentosa, and recurrent idiopathic anaphylaxis. Urine histamine levels were significantly elevated in patients with each of the three diseases when compared to histamine levels in normal subjects. However, plasma histamines were increased only in the systemic mastocytosis patients. Such elevations were persistent over the 15 to 25 weeks of followup. There was a significant relationship between plasma and urine histamine when measured concurrently. Thus, increased plasma histamine appears to differentiate systemic mastocytosis from other systemic disorders of mast cells. Scintigraphic findings in 10 cases of systemic mastocytosis were correlated to plasma histamine levels. Bone scans showed more widespread involvement than radiographs in patients with diffuse disease and detected a greater number of focal lesions. Four bone scan patterns were noted: 1) normal, 2) focal, 3) multifocal, and 4) diffuse. Plasma histamine levels were progressively greater as the scan pattern progressed from normal to diffuse. Thus, bone scintigraphy is useful in both the diagnosis and in assessing the severity of systemic mastocytosis. The value of combination H1 and H2 antihistamines or cromolyn sodium in the symptomatic relief of systemic mastocytosis was assessed. Neither drug regimen significantly differed in its efficacy, although antihistamines appeared somewhat more useful in releaving pruritis. Neither drug combination altered plasma histamine levels.